Process for imidazo[4,5-c]pyridin-4-amines

ABSTRACT

A process and intermediates for preparing 1H-imidazo[4,5-c]pyridin-4-amines are disclosed. The process includes providing a 4-phenoxy-1H-imidazo[4,5-c]pyridine and aminating the 4-phenoxy-1H-imidazo[4,5-c]pyridine to provide a 1H-imidazo[4,5-c]pyridin-4-amine.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional PatentApplication No. 60/384,558, filed May 29, 2002.

FIELD OF THE INVENTION

[0002] This invention relates to processes for preparing1H-imidazo[4,5-c]pyridin-4-amines and to intermediates for use inpreparing 1H-imidazo[4,5-c]pyridin-4-amines.

BACKGROUND OF THE INVENTION

[0003] Certain antiviral immunomodulator1H-imidazo[4,5-c]pyridin-4-amines and methods for their preparation areknown and disclosed. For example, U.S. Pat. No. 5,494,916 (Lindstrom etal.), incorporated herein by reference, discloses a method involving thesteps of forming a 1H-imidazo[4,5-c]pyridine substituted at the 4position with a hydrogenolyzable amine and hydrogenolyzing using knowncatalytic hydrogenation conditions to provide the 4-amino compound.

[0004] Methods of making certain 1H-imidazo[4,5-c]quinolin-4-amines arealso known. For example U.S. Pat. Nos. 4,689,338 and 4,929,624 (Gerster)disclose a method involving the step of heating the corresponding4-chloro compound in the presence of ammonium hydroxide or ammonia underpressure to provide the 4-amino compound. U.S. Pat. No. 4,988,815 (Andreet al.) discloses a process involving amination of the 4-position of a3-nitro-2,4-dichloroquinoline. This process too involves as a final stepthe reaction of ammonia with 4-chloro-1H-imidazo[4,5-c]quinoline. U.S.Pat. No. 5,175,296 (Gerster) discloses a process involving the reactionof a 1H-imidazo[4,5-c]quinoline 5N-oxide with an organic isocyanate andhydrolyzing the product to provide the 4-amino compound. U.S. Pat. No.5,367,076 (Gerster) discloses a process involving the reaction of a1H-imidazo[4,5-c]quinoline 5N-oxide with an acylating agent and reactingthe product with an aminating agent to provide the 4-amino compound.U.S. Pat. No. 5,395,937 (Nikolaides) discloses a process involvingamination of the 4-position of a 3-nitroquinolin-2,4-disulfonate with asubstituted amine. The final step of the process involves hydrogenolysisto provide the 4-amino compound. U.S. Pat. No. 5,741,908 (Gerster etal.) discloses a process involving the reaction of a6H-imidazo[4,5-c]tetrazolo[1,5-a] quinoline with triphenylphosphine toprovide an N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amine and asubsequent hydrolysis to provide a 1H-imidazo[4,5-c]quinoline-4-amine.

[0005] Methods of making certain 1-(substitutedaryl)alkyl-1H-imidazo[4,5-c]quinolin-4-amines,6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amines,1,6,7,8-tetrahydrocyclopenta[b]imidazo[4,5-d]pyridin-4-amines, and1,6,7,8,9,10-hexahydrocyclohepta[b]imidazo[4,5-d]pyridin-4-amines arealso known. Japanese Unexamined Patent Publication No. 11-80156discloses a process involving the reaction of the corresponding 4-chlorocompound and phenol with an alkali to form the corresponding 4-phenoxycompound, which is reacted with ammonium acetate to provide the 4-aminocompound.

[0006] Despite these developments in methods for making certainimidazoquinolin- and imidazopyridin-4-amines, there is a continuing needfor useful, alternative processes and intermediates for preparingimidazo[4,5-c]pyridin-4-amines.

SUMMARY OF THE INVENTION

[0007] This invention provides a process (I) for preparing a1H-imidazo[4,5-c]pyridin-4-amine compound of Formula I

[0008] or a pharmaceutically acceptable salt thereof wherein

[0009] R₁ is selected from hydrogen; CHR_(x)R_(y) wherein R_(x) ishydrogen and R_(y) is selected from alkyl or cyclic alkyl containing oneto ten carbon atoms, straight chain or branched chain alkenyl containingtwo to ten carbon atoms, hydroxyalkyl containing one to six carbonatoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbonatoms and the alkyl moiety contains one to six carbon atoms, benzyl, andphenylethyl; and —C═CR_(z)R_(z) wherein each R_(z) is independentlyalkyl or cyclic alkyl of one to six carbon atoms;

[0010] R₂ is selected from hydrogen; alkyl containing one to eightcarbon atoms; hydroxyalkyl containing one to six carbon atoms;alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atomsand the alkyl moiety contains one to six carbon atoms; benzyl;phenylethyl; and phenyl; the benzyl, phenylethyl, or phenyl substituentbeing optionally substituted on the benzene ring by a moiety selectedfrom methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkylmoiety contains one to four carbon atoms;

[0011] R₃ and R₄ are independently selected from hydrogen and alkyl ofone to five carbon atoms; which process comprises the steps of:

[0012] (1) providing a compound of Formula II

[0013]  wherein R₃ and R₄ are as described above;

[0014] (2) reacting the compound of the Formula II with a chlorinatingagent to provide a compound of Formula III

[0015] (3) reacting the compound of the Formula III with a compound offormula R₁NH₂, wherein R₁ is as defined above, to provide a compound ofFormula IV

[0016] (4) reacting the compound of the Formula IV with an alkali metalphenoxide to provide a compound of Formula V

[0017] (5) reducing the compound of the Formula V to provide a compoundof Formula VI

[0018] (6) reacting the compound of the Formula VI with a carboxylicacid of the formula R₂CO₂H; an equivalent thereof selected from thecorresponding acyl halide, R₂C(O-alkyl)₃, andR₂C(O-alkyl)₂(O(O═)C-alkyl); or a mixture thereof, wherein R₂ is asdefined above and each alkyl contains 1 to 8 carbon atoms, to provide acompound of Formula VIII

[0019]  and

[0020] (7) reacting the compound of the Formula VIII with an aminatingagent to provide the compound of the Formula I.

[0021] In some embodiments, in step (6) the compound of the Formula VIis reacted with the carboxylic acid of the formula R₂CO₂H; an equivalentthereof selected from the corresponding acyl halide, R₂C(O-alkyl)₃, andR₂C(O-alkyl)₂(O(O=)C-alkyl); or a mixture thereof; in the presence ofcyclization conditions to provide a compound of the Formula VIII.

[0022] In some embodiments, step (6) includes the steps of:

[0023] (6a) reacting the compound of the Formula VI with a carboxylicacid of the formula R₂CO₂H or the corresponding acyl halide to provide acompound of Formula VII

[0024]  and

[0025] (6b) subjecting the compound of the Formula VII to cyclizationconditions, during step (6a) or subsequent to the completion of step(6a), to provide a compound of the Formula VIII.

[0026] In some embodiments the above process (I) further comprises thestep of isolating the compound of the Formula I or a pharmaceuticallyacceptable salt thereof.

[0027] In another embodiment this invention provides a process (II) forpreparing a 1H-imidazo[4,5-c]pyridin-4-amine compound of the Formula I

[0028] or a pharmaceutically acceptable salt thereof wherein

[0029] R₁ is selected from hydrogen; CHR_(x)R_(y) wherein R_(x) ishydrogen and R_(y) is selected from alkyl or cyclic alkyl containing oneto ten carbon atoms, straight chain or branched chain alkenyl containingtwo to ten carbon atoms, hydroxyalkyl containing one to six carbonatoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbonatoms and the alkyl moiety contains one to six carbon atoms, benzyl, andphenylethyl; and —C═CR_(z)R_(z) wherein each R_(z) is independentlyalkyl or cyclic alkyl of one to six carbon atoms;

[0030] R₂ is selected from hydrogen; alkyl containing one to eightcarbon atoms; hydroxyalkyl containing one to six carbon atoms;alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atomsand the alkyl moiety contains one to six carbon atoms; benzyl;phenylethyl; and phenyl; the benzyl, phenylethyl, or phenyl substituentbeing optionally substituted on the benzene ring by a moiety selectedfrom methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkylmoiety contains one to four carbon atoms;

[0031] R₃ and R₄ are independently selected from hydrogen and alkyl ofone to five carbon atoms;

[0032] which process comprises the steps of:

[0033] (1) providing a compound of Formula II

[0034]  wherein R₃ and R₄ are as described above;

[0035] (2) reacting the compound of the Formula II with a chlorinatingagent to provide a compound of Formula III

[0036] (3) reacting the compound of the Formula III with a compound offormula R₁NH₂, wherein R₁ is as defined above, to provide a compound ofFormula IV

[0037] (4) reducing the compound of the Formula TV to provide a compoundof Formula IX

[0038] (5) reacting the compound of the Formula IX with a carboxylicacid of the formula R₂CO₂H; an equivalent thereof selected from thecorresponding acyl halide, R₂C(O-alkyl)₃, andR₂C(O-alkyl)₂(O(O═)C-alkyl); or a mixture thereof, wherein R₂ is asdefined above and each alkyl contains 1 to 8 carbon atoms to provide acompound of Formula XI

[0039] (6) reacting the compound of the Formula XI with an alkali metalphenoxide to provide a compound of Formula VIII

[0040]  and

[0041] (7) reacting the compound of the Formula VIII with an aminatingagent to provide a compound of the Formula I.

[0042] In some embodiments, in step (5) the compound of the Formula IXis reacted with the carboxylic acid of the formula R₂CO₂H; an equivalentthereof selected from the corresponding acyl halide, R₂C(O-alkyl)₃, andR₂C(O-alkyl)₂(O(O═)C-alkyl); or a mixture thereof; in the presence ofcyclization conditions, to provide a compound of the Formula XI.

[0043] In some embodiments, step (5) includes the steps of:

[0044] (5a) reacting the compound of the Formula IX with a carboxylicacid of the formula R₂CO₂H or the corresponding acyl halide to provide acompound of Formula X

[0045]  and

[0046] (5b) subjecting the compound of the Formula X to cyclizationconditions, during step (5a) or subsequent to the completion of step(5a) to provide a compound of the Formula XI.

[0047] In some embodiments the above process (II) further comprises thestep of isolating the compound of Formula I or a pharmaceuticallyacceptable salt thereof.

[0048] In another aspect this invention also provides compounds of theformulae

[0049] and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0050] As used herein, “alkyl” includes straight chain alkyl andbranched chain alkyl wherein the alkyl is either unsubstituted orsubstituted. For example, the alkyl portion of substituted alkyls suchas hydroxyalkyl and alkoxyalkyl includes straight chain alkyl andbranched chain alkyl.

[0051] Reaction Scheme I illustrates a process of the invention whereR₁, R₂, R₃, and R₄ are as defined above, and Ph is phenyl.

[0052] In the first step of Reaction Scheme Ia2,4-dihydroxy-3-nitropyridine of Formula II is provided. Many2,4-dihydroxy-3-nitropyridines of Formula II are known and others can bereadily prepared using known synthetic methods, see for example,Lindstrom et al., U.S. Pat. No. 5,446,153 and the documents citedtherein. In some embodiments, R₃ and R₄ in Formula II are independentlyhydrogen or methyl, and in others R₃ and R₄ are both methyl.

[0053] In step (2) of Reaction Scheme I a 2,4-dihydroxy-3-nitropyridineof Formula II is chlorinated using conventional chlorinating agents toprovide a 2,4-dichloro-3-nitropyridine of Formula III. Examples ofchlorinating agents include, but are not limited to, phosphorusoxychloride, thionyl chloride, phosgene, oxalyl chloride, and phosphoruspentachloride. In a preferred embodiment, the chlorinating agent isphosphorus oxychloride. The chlorinating agent may be used in theabsence or presence of an inert solvent such as N,N-dimethylformamide ormethylene chloride and at temperatures up to the reflux temperature. Forexample, a compound of Formula II is combined with phosphorousoxychloride and heated. The product can be isolated from the reactionmixture using conventional methods.

[0054] In step (3) of Reaction Scheme I a 2,4-dichloro-3-nitropyridineof Formula III is reacted with an amine compound of formula R₁NH₂ toprovide a 2-chloro-3-nitropyridine of Formula IV. In certain embodimentsthe compound of formula R₁NH₂ is selected from2-hydroxy-2-methylpropylamine and 2-methylpropylamine. The reaction maybe carried out in an inert solvent such as N,N-dimethylformamide ormethylene chloride in the presence or in the absence of a base such astriethylamine at a temperature up to the reflux temperature of thesolvent. For example, the reaction is carried out by adding the amine toa solution of a compound of Formula III in a suitable solvent such asN,N-dimethylformamide in the presence of a tertiary amine such astriethylamine. The product can be isolated from the reaction mixtureusing conventional methods.

[0055] In step (4) of Reaction Scheme I a 2-chloro-3-nitropyridine ofFormula IV is reacted with an alkali metal phenoxide to provide a3-nitro-2-phenoxypyridine of Formula V. For example, phenol is reactedwith sodium hydride in a suitable solvent such as diglyme to form thesodium phenoxide, and the sodium phenoxide is then reacted at anelevated temperature with a compound of Formula IV. The product can beisolated from the reaction mixture using conventional methods.

[0056] In step (5) of Reaction Scheme I the compound (a3-nitro-2-phenoxypyridine of Formula V) provided by step (4) is reducedto provide a 3-amino-2-phenoxypyridine of Formula VI. Preferably, thereduction is carried out using a conventional heterogeneoushydrogenation catalyst. The catalyst may be selected from, for example,platinum on carbon and palladium on carbon. The reaction canconveniently be carried out on a Parr apparatus in a suitable solventsuch as isopropyl alcohol or toluene. Alternatively, Ni₂B can begenerated in situ from sodium borohydride and NiCl₂ in the presence ofmethanol. The compound of Formula V is added to the reducing agentsolution to effect reduction of the nitro group. When the compound ofFormula V contains an alkenylene moiety, the Ni₂B reducing agent can beused without reducing the alkenylene moiety. The product can be isolatedfrom the reaction mixture using conventional methods.

[0057] In step (6) of Reaction Scheme I a 3-amino-2-phenoxypyridine ofFormula VI is reacted with a carboxylic acid of the formula R₂CO₂H, anequivalent thereof, or a mixture thereof, in the presence of cyclizationconditions or followed by cyclization conditions to provide a4-phenoxy-1H imidazo[4,5-c]pyridine of Formula VIII. Suitableequivalents to the carboxylic acid include compounds of the formulaR₂C(O-alkyl)₃, 1,1-dialkoxyalkyl alkanoates (R₂C(O-alkyl)₂(OOC-alkyl)),corresponding acyl halides, and mixtures thereof, wherein R₂ is asdefined above and each alkyl contains 1 to 8 carbon atoms. Thecarboxylic acid or equivalent is selected such that it will provide thedesired R₂ substituent in the compound of Formula VIII. For example,triethyl orthoformate will provide a compound where R₂ is hydrogen, andtrimethyl orthovalerate will provide a compound where R₂ is butyl. Incertain embodiments, R₂ is ethoxymethyl, and in other embodiments, R₂ isethoxymethyl when R₁ is selected from 2-hydroxy-2-methylpropyl and2-methylpropyl. In some embodiments, R₂ is ethoxymethyl when R₁ isselected from 2-hydroxy-2-methylpropyl and 2-methylpropyl, and R₃ and R₄are independently hydrogen and methyl. The reaction can be run in theabsence of solvent or in an inert solvent such as, for example, toluene,dichloromethane, acetonitrile, or pyridine. The product or apharmaceutically acceptable salt thereof can be isolated from thereaction mixture using conventional methods.

[0058] The cyclization conditions include heating to an elevatedtemperature, such as a reflux temperature, sufficient to drive off anyalcohol or water formed as a by-product of the reaction. Optionally, thepresence of a catalyst such as pyridine hydrochloride can be included inthe cyclization conditions. The cyclization reaction can be run in theabsence of a solvent or in an inert solvent such as toluene, pyridine,or other solvent, preferably, having a boiling point of at least about100° C.

[0059] In some embodiments, step (6) can be carried out by using steps(6a) and (6b) of Reaction Scheme I. In step (6a) a compound of theFormula VI is reacted with a carboxylic acid of the formula R₂CO₂H orthe corresponding acyl halide, such as R₂C(O)Cl or R₂C(O)Br, wherein R₂is as defined above, to provide anN-(4-amino-2-phenoxypyridin-3-yl)amide of Formula VII. The reaction canbe run by adding the carboxylic acid, corresponding acyl halide, ormixture thereof to the compound of Formula VI dissolved in an inertsolvent such as toluene, acetonitrile, pyridine or dichloromethane. Thereaction can be carried out at or below ambient temperature, forexample, in the range of 0 to 30° C. The product can be isolated fromthe reaction mixture using conventional methods.

[0060] In step (6b) the N-(4-amino-2-phenoxypyridin-3-yl)amide ofFormula VII is cyclized to provide a 4-phenoxy-1H imidazo[4,5-c]pyridineof Formula VIII. The cyclization can be carried out at an elevatedtemperature, such as a reflux temperature, sufficient to drive off anywater formed as a by-product of the reaction. Optionally a catalyst suchas pyridine hydrochloride can be included. The reaction can be run inthe absence of solvent or in an inert solvent such as toluene, pyridine,or other solvents, preferably having a boiling point of at least about100° C. Step (6b) may be run concurrently with step (6a) without firstisolating the product of step (6a). The product can be isolated from thereaction mixture using conventional methods. In one embodiment, the acylhalide is ethoxyacetyl chloride, and the cyclization conditions includean elevated temperature and the presence of pyridine, preferably withpyridine hydrochloride catalyst, during the reaction of the ethoxyacetylchloride with the compound of Formula VI.

[0061] In step (7) of Reaction Scheme I a4-phenoxy-1H-imidazo[4,5-c]pyridine of Formula VIII is aminated toprovide a 1H-imidazo[4,5-c]pyridine-4-amine of Formula I. In oneembodiment, the aminating agent is ammonium acetate. The reaction can becarried out by combining a compound of Formula VIII with ammoniumacetate and heating, for example, in a sealed container with heating atabout 150° C. The product or a pharmaceutically acceptable salt thereofcan be isolated using conventional methods.

[0062] In certain embodiments of the above process (I) R₁ is selectedfrom 2-hydroxy-2-methylpropyl and 2-methylpropyl.

[0063] In certain embodiments of the above process (I) R₂ isethoxymethyl.

[0064] In certain embodiments of the above process (I) R₃ and R₄ areindependently hydrogen or methyl.

[0065] In other embodiments of the above process (I) R₃ and R₄ are bothmethyl.

[0066] In some embodiments of the above process (I) R₁ is selected from2-hydroxy-2-methylpropyl and 2-methylpropyl, and R₂ is ethoxymethyl.

[0067] In some embodiments of the above process (I) R₁ is selected from2-hydroxy-2-methylpropyl and 2-methylpropyl, R₂ is ethoxymethyl, and R₃and R₄ are independently hydrogen or methyl.

[0068] In some embodiments of the above process (I), in step (6a) thecarboxylic acid equivalent is the corresponding acyl halide of R₂CO₂H,and in step (6b) the cyclization conditions include heating to anelevated temperature and a condition selected from the presence ofpyridine, and the presence of pyridine with pyridine hydrochloride.

[0069] In one embodiment of the above process (I), the acyl halide isethoxyacetyl chloride, and the cyclization conditions include anelevated temperature and the presence of pyridine during step (6a).

[0070] In another embodiment of the above process (I), the alkali metalphenoxide is sodium phenoxide.

[0071] In another embodiment of the above process (I), the chlorinatingagent is phosphorus oxychloride.

[0072] In another embodiment of the above process (I), the compound ofthe formula R₁NH₂ is selected from 2-hydroxy-2-methylpropylamine and2-methylpropylamine.

[0073] In another embodiment of the above process (I), in step (5) thecompound of Formula V is reduced with a heterogeneous hydrogenationcatalyst. For example, the heterogeneous hydrogenation catalyst isselected from platinum on carbon and palladium on carbon.

[0074] In another embodiment of the above process (I), the aminatingagent is ammonium acetate.

[0075] In some embodiments of the above process (I) the compound ofFormula I is selected from

[0076] and pharmaceutically acceptable salts thereof.

[0077] Reaction Scheme II also illustrates a process of the inventionwhere R₁, R₂, R₃, and R₄ are as defined above, and Ph is phenyl.

[0078] In the first step of Reaction Scheme II a2,4-dihydroxy-3-nitropyridine of Formula II is provided. Many2,4-dihydroxy-3-nitropyridines of Formula II are known and others can bereadily prepared using known synthetic methods, see for example,Lindstrom et al., U.S. Pat. No. 5,446,153 and the documents citedtherein. In some embodiments, R₃ and R₄ of Formula II are independentlyhydrogen or methyl, and in others R₃ and R₄ are both methyl.

[0079] In step (2) of Reaction Scheme II a 2,4-dihydroxy-3-nitropyridineof Formula II is chlorinated using conventional chlorinating agents toprovide a 2,4-dichloro-3-nitropyridine of Formula III. Examples ofchlorinating agents include, but are not limited to, phosphorusoxychloride, thionyl chloride, phosgene, oxalyl chloride, and phosphoruspentachloride. Preferably the chlorinating agent is phosphorusoxychloride. The chlorinating agent may be used in the absence orpresence of an inert solvent such as N,N-dimethylformamide ordichloromethane and at temperatures up to the reflux temperature. Forexample, a compound of Formula II is combined with phosphorousoxychloride and heated. The product can be isolated from the reactionmixture using conventional methods.

[0080] In step (3) of Reaction Scheme II a 2,4-dichloro-3-nitropyridineof Formula III is reacted with an amine compound of formula R₁NH₂ toprovide a 2-chloro-3-nitropyridine of Formula IV. In some embodiments,the compound of formula R₁NH₂ is selected from2-hydroxy-2-methylpropylamine and 2-methylpropylamine. The reaction maybe carried out in an inert solvent such as N,N-dimethylformamide ordichloromethane in the presence or in the absence of a base such astriethylamine at a temperature up to the reflux temperature of thesolvent. For example, the reaction is carried out by adding the amine toa solution of a compound of Formula III in a suitable solvent such asN,N-dimethylformamide in the presence of a tertiary amine such astriethylamine. The product can be isolated from the reaction mixtureusing conventional methods.

[0081] In step (4) of Reaction Scheme II the compound (a2-chloro-3-nitropyridine of Formula IV) provided by step (3) is reducedto provide a 3-amino-2-chloropyridine of Formula IX. Preferably, thereduction is carried out using a conventional heterogeneoushydrogenation catalyst, for example, platinum on carbon. The reactioncan conveniently be carried out on a Parr apparatus in a suitablesolvent such as isopropyl alcohol or toluene. Alternatively, Ni₂B can begenerated in situ from sodium borohydride and NiCl₂ in the presence ofmethanol. The compound of Formula V is added to the reducing agentsolution to effect reduction of the nitro group. When the compound ofFormula V contains an alkenylene moiety, the Ni₂B reducing agent can beused without reducing the alkenylene moiety. The product can be isolatedfrom the reaction mixture using conventional methods.

[0082] In step (5) of Reaction Scheme II a 3-amino-2-chloropyridine ofFormula IX is reacted with a carboxylic acid of the formula R₂CO₂H, anequivalent thereof, or a mixture thereof, in the presence of cyclizationconditions or followed by cyclization conditions to provide a4-chloro-1H imidazo[4,5-c]pyridine of Formula XI. Suitable equivalentsto the carboxylic acid include compounds of the formula R₂C(O-alkyl)₃,1,1-dialkoxyalkyl alkanoates (R₂C(O-alkyl)₂(OOC-alkyl)), correspondingacyl halides, and mixtures thereof, wherein R₂ is as defined above andeach alkyl contains 1 to 8 carbon atoms. The carboxylic acid orequivalent is selected such that it will provide the desired R₂substituent in the compound of Formula XI. For example, triethylorthoformate will provide a compound where R₂ is hydrogen, and trimethylorthovalerate will provide a compound where R₂ is butyl. In certainembodiments, R₂ is ethoxymethyl, and in other embodiments, R₂ isethoxymethyl when R₁ is selected from 2-hydroxy-2-methylpropyl and2-methylpropyl. In some embodiments, R₂ is ethoxymethyl when R₁ isselected from 2-hydroxy-2-methylpropyl and 2-methylpropyl, and R₃ and R₄are independently hydrogen and methyl. The reaction can be run in theabsence of solvent or in an inert solvent such as, for example, toluene,dichloromethane, acetonitrile, or pyridine. The product or apharmaceutically acceptable salt thereof can be isolated from thereaction mixture using conventional methods.

[0083] The cyclization conditions include heating to an elevatedtemperature, such as a reflux temperature, sufficient to drive off anyalcohol or water formed as a byproduct of the reaction. Optionally, thepresence of a chlorinating agent such as phosphorus oxychloride can beincluded in the cyclization conditions. The reaction can be run in theabsence of solvent or in an inert solvent such as toluene or othersolvents, preferably, have a boiling point of at least about 100° C.

[0084] In some embodiments step (5) can be carried out by using steps(5a) and (5b) of Reaction Scheme II. In step (5a) a compound of theFormula IX is reacted with a carboxylic acid of the formula R₂CO₂H orthe corresponding acyl halide, such as R₂C(O)C₁ or R₂C(O)Br, wherein R₂is as defined above, to provide an N-(4-amino-2-chloropyridin-3-yl)amideof Formula X. The reaction can be run by adding the carboxylic acid,corresponding acyl halide, or mixture thereof to the compound of FormulaIX dissolved in an inert solvent such as toluene, acetonitrile, pyridineor dichloromethane. The reaction can be carried out at or below ambienttemperature, for example, in the range of 0 to 30° C. Optionally, atertiary amine, for example triethylamine, is included. The product canbe isolated from the reaction mixture using conventional methods.

[0085] In step (5b) the N-(4-amino-2-chloropyridin-3-yl)amide of FormulaX is cyclized to provide a 4-chloro-1H imidazo[4,5-c]pyridine of FormulaXI. The cyclization can be carried out at an elevated temperature, suchas a reflux temperature or about 100° C. to about 150° C., for exampleabout 110° C. to about 135° C., sufficient to drive off any water formedas a by-product of the reaction. The reaction may be carried out in aninert solvent such as toluene, optionally in the presence of phosphorusoxychloride. Step (5b) may be run concurrently with step (5a) withoutfirst isolating the product of step (5a). The product can be isolatedfrom the reaction mixture using conventional methods. In one embodiment,the acyl halide is ethoxyacetyl chloride, and the cyclization conditionsinclude an elevated temperature and the presence of phosphorusoxychloride.

[0086] In step (6) of Reaction Scheme II a 4-chloro-1Himidazo[4,5-c]pyridine of Formula XI is reacted with an alkali metalphenoxide to provide a 4-phenoxy-1H-imidazo[4,5-c]pyridine of FormulaVIII. For example, phenol is reacted with sodium hydride in a suitablesolvent such as diglyme to form sodium phenoxide, and the sodiumphenoxide is then reacted at an elevated temperature with a compound ofFormula XI. The product can be isolated from the reaction mixture usingconventional methods.

[0087] In step (7) of Reaction Scheme II a4-phenoxy-1H-imidazo[4,5-c]pyridine of Formula VIII is aminated toprovide a 1H-imidazo[4,5-c]pyridine-4-amine of Formula I. For example,the aminating agent is ammonium acetate. The reaction can be carried outby combining a compound of Formula VIII with ammonium acetate andheating, for example, in a sealed container with heating at about 150°C. The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

[0088] In certain embodiments of the above process (II) R₁ is selectedfrom 2-hydroxy-2-methylpropyl and 2-methylpropyl.

[0089] In certain embodiments of the above process (II) R₂ isethoxymethyl.

[0090] In other embodiments of the above process (II) R₃ and R₄ areindependently hydrogen or methyl.

[0091] In other embodiments of the above process (II) R₃ and R₄ are bothmethyl.

[0092] In some embodiments of the above process (II) R₁ is selected from2-hydroxy-2-methylpropyl and 2-methylpropyl, and R₂ is ethoxymethyl.

[0093] In some embodiments of the above process (II) R₁ is selected from2-hydroxy-2-methylpropyl and 2-methylpropyl, R₂ is ethoxymethyl, and R₃and R₄ are independently hydrogen or methyl.

[0094] In some embodiments of the above process (II), in step (5a) thecarboxylic acid equivalent is the corresponding acyl halide of R₂CO₂H,and in step (5b) the cyclization conditions include an elevatedtemperature and the presence of phosphorus oxychloride.

[0095] In one embodiment of the above process (II), the acyl halide isethoxyacetyl chloride, and the cyclization conditions include anelevated temperature and the presence of phosphorus oxychloride.

[0096] In another embodiment of the above process (II), the alkali metalphenoxide is sodium phenoxide.

[0097] In another embodiment of the above process (II), the chlorinatingagent is phosphorus oxychloride.

[0098] In other embodiments of the above process (II), the compound ofthe formula R₁NH₂ is selected from 2-hydroxy-2-methylpropylamine and2-methylpropylamine.

[0099] In another embodiment of the above process (II), in step (4) thecompound of Formula IV is reduced with a heterogeneous hydrogenationcatalyst, for example, platinum on carbon.

[0100] In another embodiment of the above process (II), the aminatingagent is ammonium acetate.

[0101] In some embodiments of the above process (II) the compound ofFormula I is selected from

[0102] and pharmaceutically acceptable salts thereof.

[0103] The invention also provides novel compounds useful asintermediates in the synthesis of the compounds of Formula I. Thesecompounds have the structural Formula VIII

[0104] wherein R₁, R₂, R₃, R₄ are as defined above, and Ph is phenyl.Examples of these include compounds of the formulae

[0105] and pharmaceutically acceptable salts thereof.

[0106] The invention is further described by the following examples,which are provided for illustration only and are not intended to belimiting in any way.

EXAMPLES Example 1

[0107] Part A

[0108] 4-Hydroxy-5,6-dimethyl-2(1H)-pyridone

[0109] Ammonium hydroxide (558 ml) was added to ethyl2-methylacetoacetate (111.66 g), and the mixture was stirred for 23 h.The resulting mixture was filtered using vacuum filtration, and theresulting crystals were washed twice with small portions of distilledwater. The crystals were dried overnight in a desiccator under vacuum,yielding 46.134 g product. The filtrate was mixed with ammoniumhydroxide (40 ml), and after stirring for about 3 days, the resultingsupersaturated solution was cooled in an ice/salt/methanol bath withstirring. The resulting crystals were filtered, washed, and dried asabove, yielding 0.9536 g ethyl 3-imino-2-methylbutanoate.

[0110] Dichloromethane (800 ml), triethylamine (50.30 ml) and 46.9716 gof the combined product from above were mixed together and cooled withan ice bath. Methyl 3-chloro-3-oxopropionate was added dropwise to theresulting solution. When addition was complete the bath was removed, andthe resulting mixture was allowed to stir. After about 36 hours theresulting mixture was filtered to remove the precipitated salt. Thefiltrate was extracted with water (3×100 ml), dried with magnesiumsulfate powder, and stored under nitrogen. The resulting dried solutionwas filtered, and the filtrate was concentrated under reduced pressure.Hexane (60 ml) was added to the resulting concentrate, and solvent againwas removed under reduced pressure. The resulting amber solution waspassed through a 3.8 cm diameter, 2.5 cm plug of silica using 30:70ethyl acetate/hexane (2×250 ml) as the eluant. Solvent was strippedunder reduced pressure from the resulting solution, and the resultingoil was dissolved in 70/30 hexane/ethyl acetate (150 ml) and passedthrough a second column (3.8 cm diameter, 13-15 cm plug of silica) using70/30 hexane/ethyl acetate (750 ml) as the eluant. The solvent wasremoved from the resulting solution under reduced pressure. Theresulting product was put under high vacuum for 1 hour, yielding 77.218g of ethyl (3E)-3-[(3-methoxy-3-oxopropanoyl)imino]-2-methylbutanoate,and stored under nitrogen.

[0111] The above amide product (77.218 g) in tetrahydrofuran (THF) (250ml) was added dropwise to a mechanically stirred sodium hydride (NaH)solution, prepared by washing NaH (60% dispersion in oil) (25.601 g)with hexane (200 ml) and THF (100 ml) and then adding 575 ml of THF tothe washed NaH. When addition was complete the reaction mixture wasdivided into two portions. Each portion was refluxed in a water bath for3 hours when the reaction was quenched by addition of methanol (150 ml)to each resulting reaction mixture portion. The solvent was removedunder reduced pressure from one portion, and the resulting solid (25.541g of tan/brown powder) was combined with HCl (37%) (250 ml) and broughtto reflux for 7 hours. The resulting dark solution was brought to a pHof about 7-8 with ammonia, and the resulting crystalline powder wasfiltered off and washed with water, resulting in 5.708 g of light tanpowder, which was used in the next step.

[0112] The solvent was removed under reduced pressure from the otherportion, and the resulting solid (88.4 g) was combined with HCl (37%)(880 ml) and brought to reflux for 11 hours. The resulting reactionmixture was cooled to room temperature, brought to a pH of about 7-8with ammonium hydroxide, cooled in an ice bath, and vacuum filtered. Theresulting solid was stored in a vacuum desicator for later use in thenext step.

[0113] Part B

[0114] 2,4-Dihydroxy-5,6-dimethyl-3-nitropyridine

[0115] Nitric acid (65-71%) (2.95 ml) was added dropwise to a mixture of4-hydroxy-5,6-dimethyl-2(1H)-pyridone (5.698 g) and acetic acid (about100 ml) at about 100° C. The resulting solution was refluxed for 30minutes and then cooled to room temperature. The resulting mixture wasfiltered, the resulting crystals allowed to air dry, and the solventremoved from the filtrate under reduced pressure. Water (60 ml) wasadded to the concentrated filtrate, and the resulting crystals werefiltered and dried in a vacuum desiccator.

[0116] The above nitration process was essentially repeated using 23.612g 4-hydroxy-5,6-dimethyl-2(1H)-pyridone, 460 ml acetic acid, 12.2 mlnitric acid, and cooling the mixture in an ice bath after refluxing andprior to filtration. Combined product was used in the next step.

[0117] Part C

[0118] 2,4-Dichloro-5,6-dimethyl-3-nitropyridine

[0119] 2,4-Dihydroxy-5,6-dimethyl-3-nitropyridine from Part B (31.081 g)was combined with phosphorus oxychloride (310 ml) and brought to refluxfor 1.5 hour. The resulting mixture was slowly cooled to roomtemperature with protection from moisture and then concentrated to asolid under reduced pressure. The solid was extracted with ethyl acetate(200 ml, 2×100 ml). The combined extracts were dried with magnesiumsulfate and concentrated under reduced pressure. The resulting crudeproduct was passed through a 3.8 cm diameter by 5 cm plug of silica gel,and the resulting purified crystals (16.080 g) were used in the nextstep.

[0120] Part D

[0121]1-[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]-2-methylpropan-2-ol

[0122] Triethylamine (15.20 ml) was added to a solution of2,4-dichloro-5,6-dimethyl-3-nitropyridine (16.080 g) indimethylformamide (160 ml), and then 2-hydroxy-2-methylpropylamine(7.143 g) was added with stirring. After 1 day the resulting mixture wascooled to about 5° C. After 4 days the solvent was removed under reducedpressure, and the resulting oil was dissolved in ethyl acetate (200 ml).The resulting solution was extracted with water (3×65 ml), and thecombined aqueous layers were extracted with ethyl acetate (50 ml). Thecombined organic layers were dried with magnesium sulfate, and thesolvent was removed under reduced pressure. The crystals that formedupon cooling were recrystallized from 1:1 hexane/ethyl acetate and thenfrom ethyl acetate. The resulting purified crystals were used in thenext step.

[0123] Part E

[0124]1-[(2,3-Dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]-2-methylpropan-2-ol

[0125] A solution of sodium phenoxide was prepared by washing NaH (60%in oil) (0.412 g) with hexane (20 ml), adding diglyme (5 ml) to thewashed NaH, slowly adding phenol (0.911 g) in diglyme (15 ml) to theNaH, and stirring the resulting mixture for 30 minutes.1-[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]-2-methylpropan-2-ol(2.406 g) dissolved in 20 ml diglyme was slowly added to the phenoxidesolution. After addition was complete, the resulting mixture wasrefluxed for 4 hours and cooled to room temperature. The solvent wasremoved under reduced pressure. The resulting residue was dissolved inethyl acetate, and the ethyl acetate solution was extracted with 1Npotassium hydroxide (30 ml). The solvent was removed from the organiclayer under reduced pressure, and the resulting product pushed through aplug of silica using 3:1 hexane/ethyl acetate as the eluant.

[0126] The above was essentially repeated as follows: A solution ofsodium phenoxide was prepared by washing NaH (60% in oil) (1.654 g) withhexane (75 ml), adding diglyme (20 ml) to the washed NaH, adding phenol(3.882 g) in diglyme (50 ml) to the NaH, and stirring the resultingmixture for 30 minutes.2-Chloro-4-[(2-hydroxy-2-methylpropyl)amino]-5,6-dimethyl-3-nitropyridine(9.609 g) dissolved in 80 ml diglyme was slowly added dropwise to thephenoxide solution. After addition was complete, the resulting mixturewas refluxed overnight and then cooled. The solvent was removed underreduced pressure. The resulting residue was dissolved in ethyl acetate(200 ml), and the ethyl acetate solution was extracted with IN potassiumhydroxide (KOH) (30 ml). The resulting organic layer was combined withthe product of the above preparation, and the solvent was removed fromthe combined solution under reduced pressure. The resulting product wasrun through a silica column using 5:1 hexane/ethyl acetate as theeluant, and the solvent was removed under reduced pressure from theresulting solution to provide 7.213 g of product used in the next step.

[0127] Part F

[0128]1-[(3-Amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]-2-methylpropan-2-ol

[0129] To a 500 ml Parr hydrogenation flask was added 5% platinum oncarbon (1.432 g) and a solution of1-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]-2-methylpropan-2-olin 90/10 toluene/isopropanol (105 ml). The flask was evacuated until thesolvent bubbled, and hydrogen was pressured into the flask at 207 kPa.After three evacuation cycles the flask was pressurized with hydrogen to345 kPa and mixed on a shaker for about 2 hours. The pressure wasreleased, and thin layer chromatography (TLC) monitoring of the reactionmixture indicated complete reaction. The reaction mixture was filtered,and the solvent was removed under reduced pressure. The resultingproduct was used in the next step.

[0130] Part G

[0131]1-[2-(Ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]-2-methylpropan-2-ol

[0132] To the product from Part F(1-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-ylamino]-2-methylpropan-2-olwas added 10 ml of pyridine. Ethoxyacetyl chloride (3.014 g) was addeddropwise to the resulting mixture. The resulting solution was brought toreflux for about 3 days with an intervening day of cooling at about 5°C. The solvent was removed under reduced pressure, and the resultingproduct dissolved in ethyl acetate containing sodium bicarbonate. Theresulting mixture was extracted with water. The resulting organic layerwas dried with magnesium sulfate, the solvent was removed under reducedpressure, and the product was cooled to about 5° C. The resulting solidwas recrystallized from ethyl acetate. The supernatant was concentratedunder reduced pressure to the point of crystallization. This wasrepeated, resulting in a total of three fractions of crystals in theamounts of 1.500 g, 2.370 g, and 1.527 g, respectively.

[0133] Part H

[0134]1-[4-Amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]-2-methylpropan-2-ol

[0135] The three product fractions from Part G(1-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]-2-methylpropan-2-ol)were divided and placed in 25×150 mm culture tubes, to each of whichammonium acetate was added as shown in the following table. Culture TubeProduct Placed in Fraction Number Culture Tube (g) NH₄OAc (g) 1 1 1.46415.136 2 2 1.007 13.327 2 3 1.333 10.050 3 4 0.981 10.269 3 5 0.4655.326 1, 2, and 3 6 0.144 1.536 Container Rinse

[0136] The tubes were heated in an oil bath at 150° C. for about 36hours. After cooling to room temperature, to each tube was added 6 mlsaturated sodium carbonate solution, and sufficient water to clarify.Each tube was extracted with dichloromethane (4×10 ml). All extractswere combined and extracted with 5% KOH. The KOH extracts were extractedwith dichloromethane (2×25 ml). The organic layers were combined andconcentrated under reduced pressure. The resulting product was subjectedto column chromatography with elution solvents as follows:dichloromethane, 40:1, 20:1, 10:1, 5:1, 2:1 dichloromethane/methanol,and methanol. After cooling the resulting fractions below 0° C. forabout 1 day, the fractions were combined, concentrated under reducedpressure, dissolved in a minimum amount of methanol, and treated with 1N HCl in diethyl ether. The resulting precipitate was centrifuged, theliquid decanted off, the solid re-suspended in 50:50 methanol/diethylether, and re-centrifuged twice, pouring off the remaining liquid eachtime. After storage at below 0° C., the resulting product was dissolvedin deionized water, and passed through a C-18 cartridge (Waters, SepPak,1 g), which was then rinsed with 2:1 water/methanol containing 1% aceticacid (50 ml). The resulting solution was concentrated under reducedpressure, precipitated with saturated sodium carbonate solution,centrifuged, washed and re-centrifuged, dissolved in dichloromethane(400 ml), extracted w 10% aqueous sodium hydroxide (100 ml),concentrated under reduced pressure, and stored in a vacuum desiccator,to provide a loose powder (2.627 g), m.p. 190.5-192.9° C.

[0137] Analysis: Calculated for C₁₅H₂₄N₄O₂: %C, 61.62; %H, 8.27; %N,19.16

[0138] Found: %C, 61.39; %H, 8.31; %N 19.13

Example 2

[0139] Part A

[0140] 2,4-Dichloro-6-methyl-3-nitropyridine

[0141] Phosphorus oxychloride (500 ml) and2,4-dihydroxy-6-methyl-3-nitropyridine (50.0 g) were combined and heatedat 90° C. for 16 hours. The reaction mixture was cooled and thephosphorus oxychloride was removed under reduced pressure. The resultingblack oil was dissolved in diethyl ether and water (2 L) (added withcare). The aqueous layer was separated, made basic with sodiumcarbonate, and washed with diethyl ether (5×1 L). The combined organiclayers were dried with magnesium sulfate and concentrated under reducedpressure. The resulting black needles were extracted with hot heptane.The hot heptane solution was filtered, and the heptane was removed toproduce light brown needles (46.71 g), which were pure by NMR analysis.

[0142] Part B

[0143] 2-Chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine

[0144] 2,4-Dichloro-6-methyl-3-nitropyridine (39.5 g) from Part A andanhydrous dimethylformamide (400 ml) were combined and cooled to 0° C.Triethylamine (26.6 ml) and then 2-methylpropylamine (20.9 ml) wereadded to the resulting mixture with mixing. The reaction was completeafter 16 hours, as determined by high pressure liquid chromatography(HPLC) and TLC monitoring. The dimethylformamide was removed from theresulting reaction mixture under reduced pressure, and the resultingdark yellow oil was dissolved in ethyl acetate (800 ml). The ethylacetate solution was washed with water (3×400 ml), dried with magnesiumsulfate, and the solvent was removed under reduced pressure. Theresulting dark orange oil was dissolved in hexane (400 ml) and cooled tobelow 0° C. A seed crystal was added, and after 2 hours the resultingcrystals were filtered and washed with cold (<0° C.) hexane. Thecrystals (30.49 g) were found to be pure by NMR analysis.

[0145] Part C

[0146] N-(2-Methylpropyl)-6-methyl-3-nitro-2-phenoxypyridin-4-amine

[0147] A solution of sodium phenoxide was prepared by adding phenol(11.57 g) in portions over a period of 0.5 hour to a solution of diglyme(42 ml) and sodium hydride (60% in oil) (5.20 g). After 0.5 hour,2-chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine (28.26 g)from Part B was added to the sodium phenoxide solution, and theresulting green mixture was heated to 60° C. to dissolve the startingmaterial. After 15 minutes when the reaction was found by TLC and HPLCto be complete, any remaining sodium hydride was quenched by theaddition of methanol (25 ml) with stirring. After stirring for 20minutes, the methanol was removed from the resulting solution underreduced pressure, and the remaining dark green solution was poured intocold water (400 ml). The resulting mixture, containing a dark brownsolid, was stirred for 1.5 hours, and the solid was filtered, washedwith excess water, and allowed to dry. The solid was dissolved in ethylacetate, and the ethyl acetate solution was dried with magnesium sulfateand concentrated to a brown oil under reduced pressure. The brown oilwas placed under high vacuum for one hour and then triturated withhexane (250 ml). The resulting brownish red platelets (32.47 g) werefiltered off and dried. NMR analysis indicated pure product.

[0148] Part D

[0149] N⁴-(2-Methylpropyl)-6-methyl-2-phenoxypyridin-3,4-diamine

[0150] Toluene (150 ml), 5% platinum on carbon (1.55 g), andN-(2-methylpropyl)-6-methyl-3-nitro-2-phenoxypyridin-4-amine (31.00 g)from Part C were placed in a Parr hydrogenation flask at a hydrogenpressure of 345 kPa for 2 hours with shaking. The reaction was monitoredby TLC and HPLC. More 5% platinum on carbon (5 g) was added. After 2hours, another 4 g of 5% platinum on carbon was added and the reactionwas continued overnight. The resulting reaction mixture was filtered,and the solvent was removed from the filtrate under reduced pressure.After one hour the resulting brown oil solidified. NMR analysis of thesolid (26.37 g) indicated sufficient purity for carrying the product onto the next step.

[0151] Part E

[0152]2-Ethoxy-N-[(4-(2-methylpropylamino)-6-methyl-2-phenoxypyridin-3-yl)acetamide

[0153] Anhydrous dichloromethane (750 ml) andN4-(2-methylpropyl)-6-methyl-2-phenoxypyridin-3,4-diamine (26.00 g) fromPart D were combined with stirring under a nitrogen atmosphere, andcooled to 0° C. Triethylamine (13.4 ml) was added to the resultingmixture, followed by the slow addition over a period of 15 minutes ofethoxyacetyl chloride (11.74 g) dissolved in anhydrous dichloromethane(50 ml). After 15 minutes TLC monitoring indicated completion of thereaction, and the resulting reaction mixture was washed with water(3×500 ml). The organic layer was dried with magnesium sulfate andconcentrated to a brown oil under reduced pressure. After drying underhigh vacuum, NMR analysis of the oil (32.92 g) indicated desired productof good purity.

[0154] Part F

[0155]2-(Ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-H-imidazo[4,5-c]pyridine

[0156]2-Ethoxy-N-[(4-(2-methylpropylamino)-6-methyl-2-phenoxypyridin-3-yl)acetamide(31.50 g), pyridine HCl (10 g), and pyridine (250 ml) were combined andheated to reflux. The reaction was monitored by HPLC and TLC. After 24hours an additional 10 g of pyridine HCl was added to the reactionmixture. After 48 hours the reaction was 50% complete, and a dean starktrap was used to remove 100 ml of pyridine (with) water. Pyridine (100ml) and pyridine HCl (5 g) were added to the reaction mixture. After 36hours the reaction was ⅔ complete, and additional pyridine was removedwith the trap, followed by the addition of fresh replacement pyridine tothe reaction mixture. After 5 days, the reaction was complete. Thepyridine was removed from the reaction mixture under reduced pressure.Ethyl acetate (900 ml) was added to the resulting concentrate, and theresulting solution was washed with water (3×300 ml). The organic layerwas dried with magnesium sulfate and concentrated to a dark amber oil(27.12 g) under reduced pressure. This oil was used in the next step.

[0157] Part G

[0158]2-(Ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amineHydrochloride

[0159] The oil from Part F (26.5 g) was combined with ammonium acetate(265 g) in a flask and heated to 150° C. in an oil bath. A paper towelwas placed in the mouth of the flask to contain the subliming ammoniumacetate without allowing excessive pressure in the flask. After 24 hoursthe reaction was complete by TLC and HPLC analysis. The reaction mixturewas allowed to cool to room temperature, and the resulting dark brownoil was dissolved in chloroform (500 ml). The chloroform solution waswashed with 10% aqueous sodium hydroxide (500 ml). The aqueous layer waswashed with chloroform (500 ml), and the organic layers were combined,washed with water (350 ml), dried with magnesium sulfate, andconcentrated to a brown oil (26 g) under reduce pressure. The oil wasdissolved in isopropyl alcohol (80 ml) and salted with one equivalent ofHCl (79.5 ml of 1M HCl in diethyl ether). A solid formed after one hour.The resulting mixture was cooled to below 0° C. for two hours, and theresulting white solid was filtered off, washed with cold isopropylalcohol, and then with diethyl ether. The resulting white solid (15 g)was dissolved in ethanol (30 ml) with heating, and the solution wascooled to room temperature and seeded. Crystals slowly formed, and thesolution was cooled to about 5° C. The resulting crystals were filteredoff, washed with cold ethanol, and then with diethyl ether. The crystalswere then crushed and dried overnight under vacuum at 80° C. to provide10.01 g of2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-aminehydrochloride, m.p. 181.0-183.0° C.

[0160] Analysis: Calculated for C₁₄H₂₂N₄O (1.00 HCl): %C, 56.27; %H,7.76; %N, 18.75

[0161] Found: %C, 56.37; %H, 7.85; %N, 18.82.

Example 3

[0162] Part A

[0163] 2,4-Dichloro-6-methyl-3-nitropyridine

[0164] Phosphorus oxychloride (2000 ml) and2,4-dihydroxy-6-methyl-3-nitropyridine (200.0 g) were combined in aflask equipped with a 20% sodium hydroxide scrubber and heated withmixing at 80° C. for 16 hours. HPLC monitoring indicted that thereaction was complete. The black reaction mixture was cooled to roomtemperature, and the phosphorus oxychloride was removed under reducedpressure. The resulting black oil was slowly poured into water (1500 ml)with stirring, while not exceeding a temperature of 60° C. After coolingovernight, the resulting aqueous mixture was washed with chloroform(5×1L). The organic layers were combined, dried with magnesium sulfate,and concentrated under reduced pressure to a brown oil. The oil wasdissolved in ethyl acetate (1L), and the resulting solution was washedwith a 20% aqueous sodium carbonate solution (500 ml). A white solidformed and was filtered off. The filtrate was dried with magnesiumsulfate and concentrated under reduced pressure to a brown solid. Thesolid was recrystallized from n-heptane (400 ml) to produce light browncrystals (175 g), which were used in the next step.

[0165] Part B

[0166] 2-Chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine

[0167] Product from Part A (2,4-Dichloro-6-methyl-3-nitropyridine) (125g) and anhydrous dimethylformamide (625 ml) were combined in a nitrogenatmosphere with stirring and cooling to 0° C. Triethylamine (84.2 ml)was added, and then 2-methylpropylamine (66 ml) was added dropwise overa period of 1 hour to the resulting mixture. The reaction mixture wasstirred overnight. The reaction was found to be complete by HPLC andTLC. The reaction mixture was filtered, and the dimethylformamide wasremoved under reduced pressure. The resulting yellow oil was dissolvedin ethyl acetate (750 ml), and the resulting solution was washed withwater (3×1 L), dried with magnesium sulfate, and concentrated underreduced pressure to a yellow oil. This yellow oil was dissolved inhexane (300 ml) with heating. The resulting solution was cooled to below0° C. and after 10 minutes seeded with crystals. After 4 hours theresulting crystals were filtered off, washed with cold hexane (<0° C.),and dried at room temperature under vacuum. The resulting crystals (98g) were found to be pure by NMR analysis.

[0168] The above was essentially repeated using 466 g starting material,2.5 L anhydrous dimethylformamide, 314 ml triethylamine, and 246 ml2-methylpropylamine to provide 375 g of crystals.

[0169] Part C

[0170] N-(2-Methylpropyl)-6-methyl-3-nitro-2-phenoxypyridin-4-amine

[0171] A solution of sodium phenoxide was prepared by adding phenol (192g) dissolved in diglyme (250 ml) dropwise over a period of 1 hour to acooled (5° C.) solution of diglyme (500 ml) and sodium hydride (60% inoil) (86 g) with a nitrogen sweep and mechanical stirring. Hydrogen gaswas given off and the reaction exothermed to 24° C. After evolution ofhydrogen subsided (0.5 hour),2-chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine (470 g) fromPart B was added to the sodium phenoxide solution, and the resultinggreen mixture was heated to 60° C. for 0.5 hour. The reaction was foundby TLC and HPLC to be complete and allowed to cool. The reaction mixturewas then slowly poured into mechanically stirred, cold water (5L). After2 hours, the resulting brown solid was filtered off, washed with excesswater, and partially dried under high vacuum. The resulting solid wasdissolved in ethyl acetate (3 L), and the solution dried with magnesiumsulfate. The solvent was removed, leaving a dark brown solid, which wasdivided in two parts. Each part was mixed with hexane (1.5 L), and theresulting mixtures heated to reflux, filtered, cooled to roomtemperature, seeded with crystals, and cooled to below 0° C. overnight.The resulting light orange crystals were filtered off, washed with cold(<0° C.) hexane, and dried under vacuum at 60° C. overnight. NMRanalysis of the dried crystals (538 g) indicated pure product.

[0172] Part D

[0173] N⁴-(2-Methylpropyl)-6-methyl-2-phenoxypyridin-3,4-diamine

[0174] N-(2-Methylpropyl)-6-methyl-3-nitro-2-phenoxypyridin-4-amine (530g) from Part C was dissolved in warm toluene (2.5 L). 5% Platinum oncarbon (50 g) wetted with toluene was added to the resulting solutionunder a nitrogen atmosphere. The resulting mixture was placed in ahydrogenator, flushed multiple times with hydrogen, and filled to ahydrogen pressure of 345 kPa. The reaction was monitored by TLC andHPLC. The reaction mixture turned warm after 30 minutes, and was allowedto cooled to room temperature over 3 hours. The reaction was complete,and the resulting reaction mixture was filtered through a CELITE pad,washed with hot toluene (2 L). The CELITE pad was also washed withisopropyl alcohol. The solvent was removed from the filtrate underreduced pressure, and the resulting black oil was dissolved indichloromethane. The resulting solution was washed with water (3×1 L),dried with magnesium sulfate, and concentrated under reduced pressure toa green solid (427 g). NMR analysis of the solid indicated sufficientpurity for carrying the product on to the next step.

[0175] Part E

[0176]2-Ethoxy-N-[(4-(2-methylpropylamino)-6-methyl-2-phenoxypyridin-3-yl)acetamide

[0177] Dichloromethane (2 L) andN⁴-(2-methylpropyl)-6-methyl-2-phenoxypyridin-3,4-diamine (105 g) werecombined with mechanical stirring under a nitrogen atmosphere, andcooled to 3° C. with an ice bath. Ethoxyacetyl chloride (47.4 g)dissolved in dichloromethane (500 ml) was added dropwise to theresulting mixture over 40 minutes. After the addition was completed theice bath was removed. After one hour when TLC analysis of the reactionmixture indicated completion, the resulting reaction mixture was washedwith water (3×1 L). The organic layer was dried with magnesium sulfateand concentrated to a black oil under reduced pressure. NMR analysis ofthe oil indicated desired product of good purity.

[0178] The above was repeated three times to provide a total of 541 g ofproduct.

[0179] Part F

[0180]2-(Ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine

[0181]2-Ethoxy-N-[(4-(2-methylpropylamino)-6-methyl-2-phenoxypyridin-3-yl)acetamide(525 g), pyridine HCl (250 g), and pyridine (3.75 L) were combined undera nitrogen atmosphere and with mechanical stirring and heated to reflux.The reaction was monitored daily for 7 days by HPLC. Each day anadditional 50 g of pyridine HCl was added, 500 ml of pyridine wasremoved from the reaction mixture using a dean stark trap, and 500 ml offresh pyridine was added. After 7 days, the reaction was complete, andthe resulting reaction mixture was cooled to room temperature. Somepyridine HCl precipitated out. This was filtered off and washed withethyl acetate. The combined filtrate and ethyl acetate wash wasconcentrated to a black oil under reduced pressure. The oil wasdissolved in ethyl acetate (4 L), and the resulting solution was dividedinto equal parts, each of which was washed with water (3×1 L). Thecombined organic layers were dried with magnesium sulfate andconcentrated to a black oil under reduced pressure. This oil was driedunder high vacuum to provide 460 g of product. NMR analysis of the driedoil indicated good purity, and the oil was used in the next step.

[0182] Part G

[0183]2-(Ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amineEthanesulfonate

[0184] The oil from Part F (200 g)(2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine)was combined with ammonium acetate (2 kg) in a flask equipped with amechanical stirrer and Claisen adaptor and heated to 140° C. A papertowel was placed in the open neck of the flask and one neck of theClaisen adaptor to allow the gases to escape while retaining most of theammonium acetate. After mixing overnight the reaction was complete asdetermined by HPLC analysis. The reaction mixture was allowed to cool toroom temperature, and was then slowly poured into a 25% aqueous sodiumhydroxide solution. The resulting mixture (pH 13-14) was allowed to cooland was split into two portions. Each portion was washed with chloroform(2×1 L). The chloroform layers were combined, dried with magnesiumsulfate, and concentrated under reduced pressure to a black oil, whichsolidified. The black oil was dissolved in chloroform (2 L), and theresulting solution was washed with water (1 L), dried with magnesiumsulfate, and concentrated to a black oil.

[0185] The above process was repeated using 201 g of2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine.The resulting black oil was combined with the above black oil to give322 g, which by NMR analysis was approximately 90% pure. The oil wasdissolved in isopropyl alcohol (1.3 L) with heat. To the resultingsolution cooled to 15° C. was slowly added 1067 ml 1 M HCl in diethylether with mechanical stirring over a one hour period. The resultingreaction mixture maintained a constant temperature with cooling with anice bath. A white solid formed, and after the addition was complete theice bath was removed and stirring was continued for one hour. Theresulting mixture was filtered, and the solid was washed with isopropylalcohol (2 L) and diethyl ether (1 L). The resulting white solid wasdried overnight under vacuum at 80° C. to provide 268 g of the HCl salt.The HCl salt was split into two portions, and each portion was heated toreflux in isopropyl alcohol (1.2 L). After the HCl salt dissolved, thesolutions were cooled, causing white crystals to form. After cooling for2 hours at about 5° C., the solid was filtered off and washed with coldisopropyl alcohol (2 L). The white solid was dried under vacuum at 80°C. to give 238 g of HCl salt, that was pure by NMR analysis.

[0186] The HCl salt was dissolved in water (2.3 L) with mechanicalstirring. Sodium carbonate (230 g) was added to the resulting solution,causing a light brown oil to separate from the water. After 2 hourschloroform (1 L) was added to the mixture, and the organic layer wasseparated, washed with water (1 L), dried with sodium sulfate, andconcentrated under reduced pressure to a light brown oil (212 g).

[0187] The oil was dissolved in isopropyl alcohol (800 ml) with heat. Tothe resulting mechanically stirred solution was added 95% ethansulfonicacid (65 ml) slowly over a 20 minute period. The temperature of thereaction mixture increased from 30° C. to 49° C. when the addition wascomplete. A white solid separated out and the resulting reaction mixturewas cooled by ice bath with continued mixing for 1 hour. The white solidwas filtered off, washed with cold isopropyl alcohol (2 L) and diethylether (1 L), and dried overnight under vacuum at 80° C., to provide 268g of2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amineethanesulfonate, m.p. 183.0-185.0° C.

[0188] Analysis: Calculated for C₁₄H₂₂N₄O (1.00 C₂H₆SO₃): %C, 51.59; %H,7.58; %N, 15.04

[0189] Found: %C, 51.59; %H, 7.51; %N, 14.99.

Example 4

[0190] Part A

[0191] 2-Chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine

[0192] 2,4-Dichloro-6-methyl-3-nitropyridine (28.75 g) and anhydrousdimethylformamide (300 ml) were combined and cooled to 0° C.Triethylamine (19.4 ml) and then 2-methylpropylamine (13.8 ml) wereadded to the resulting mixture. The reaction was not complete asdetermined by HPLC and TLC after 16 hours. An additional 1.38 ml of2-methylpropylamine was added to the reaction mixture, and after anotherhour the reaction was complete. The dimethylformamide was removed fromthe resulting reaction mixture under reduced pressure, and the resultingdark yellow oil was dissolved in ethyl acetate. The ethyl acetatesolution was washed with water (3×), dried with magnesium sulfate, andthe solvent was removed under reduced pressure. The resulting yellow oilwas dissolved in hexane and cooled to below 0° C. overnight. A yellowsolid formed. The yellow solid was washed with cold (<0° C.) hexane andfiltered. The remaining crystals (22.02 g) were found to be pure by NMRanalysis and used in the next step.

[0193] Part B

[0194] 2-Chloro-N⁴-(2-methylpropyl)-6-methylpyridin-3,4-diamine

[0195] 2-Chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine(21.95 g) from Part A, toluene (200 ml), and 5% Platinum on carbon (2.20g) were placed in a hydrogenator at a hydrogen pressure of 345 kPa for 2hours. The reaction, monitored by HPLC, was complete, and the resultingreaction mixture was filtered through a fluted filter paper and thenthrough a folded No. 2 Whatman filter. The solvent was removed from thefiltrate under reduced pressure, and the resulting brown oil solidifiedafter one hour. NMR analysis of the solid indicated sufficient purityfor carrying the product (19.03 g) on to the next step.

[0196] Part C

[0197]N-[2-Chloro-4-(2-methylpropylamino)-6-methylpyrdin-3-yl]-2-ethoxyacetamide

[0198] Anhydrous dichloromethane (750 ml) and2-chloro-N⁴-(2-methylpropyl)-6-methylpyridin-3,4-diamine (18.84 g) werecombined and cooled to 0° C. Triethylamine (12.9 ml) was added dropwiseto the resulting mixture, and then ethoxyacetyl chloride (11.34 g)dissolved in anhydrous dichloromethane (50 ml) was added slowly to theresulting mixture, which turned dark. After two hours the dark mixturewas allowed to warm to room temperature. TLC analysis of the reactionmixture indicated completion, and the solvent was removed under reducedpressure. The resulting yellow solid was dissolved in chloroform, andthe resulting solution was washed with water. The organic layer wasdried with magnesium sulfate and concentrated to a dark brown oil (27.75g) under reduced pressure. NMR analysis of the oil indicated desiredproduct of suitable purity for use in the next step.

[0199] Part D

[0200]4-Chloro-2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridine

[0201]N-[2-Chloro-4-(2-methylpropylamino)-6-methylpyrdin-3-yl]-2-ethoxyacetamide(26.43 g), anhydrous toluene (400 ml), and phosphorus oxychloride (74ml) were combined and heated to 110° C. for 16 hours. HPLC analysis ofthe resulting reaction mixture indicated 30% completion. The reactionmixture was heated to reflux for an additional 24 hours when thereaction was found to be complete. The resulting reaction mixture wascooled, and the phosphorus oxychloride and toluene were removed underreduced pressure. The resulting black oil was dissolved in ethyl acetateand water, and the aqueous layer was made basic with sodium carbonate.The basic aqueous layer was washed with ethyl acetate (2×). The organiclayers were combined, dried with magnesium sulfate, and concentrated toa black oil under reduced pressure. The oil was extracted with hothexane. The resulting hexane solution was filtered hot, and the filtratewas cooled to below 0° C. overnight. The resulting orange and blackcrystals were washed with cold hexane. NMR analysis of the resultingproduct (14.02 g) indicated only minor impurities, and the product wascarried on to the next step.

[0202] Part E

[0203]2-(Ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine

[0204] To a chilled solution of diglyme (3 ml) and sodium hydride (60%in oil) (0.075 g) was added phenol (0.17 g) in portions. Hydrogen wasgiven off and the reaction was continued 0.5 hour until the bubblingstopped.4-Chloro-2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridine(0.47 g) from Part D dissolved in diglyme (2 ml) was added dropwise tothe resulting reaction mixture. When addition was complete the resultingdark brown reaction solution was heated to reflux. After 48 hours, HPLCanalysis indicated no further reaction. The solvent was removed from theresulting reaction solution under reduced pressure, and the resultingblack oil was dissolved in dichloromethane. The dichloromethane solutionwas washed with 5% aqueous sodium hydroxide (100 ml), and the resultingbasic aqueous layer was washed with dichloromethane (2×). The organiclayers were combined, dried with magnesium sulfate, and concentrated toa black oil under reduced pressure.

[0205] The above process was repeated using 50 ml diglyme, 2.15 g sodiumhydride (60% in oil), 4.80 g phenol, and 13.55 g starting material. Theresulting black oil was combined with that from the above process andpassed through a column of silica using 20/80 ethyl acetate/hexane.After removing the solvent under reduced pressure from the elutedsolution, NMR analysis of the resulting yellow oil (9.30 g) indicatedpure product, which was used in the next step.

[0206] Part F

[0207]2-(Ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amineHydrochloride

[0208] A sealed glass tube containing2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine(9.07 g) from Part E and ammonium acetate (80 g) was heated to 150° C.with stirring. After 2 days HPLC and TLC monitoring indicated formationof the 4-hydroxy impurity at 6% and that the reaction was complete. Theresulting reaction mixture was cooled to room temperature, and theresulting dark amber oil was dissolved in chloroform (500 ml). Thechloroform solution was washed with 10% aqueous sodium hydroxide (357ml). The resulting basic aqueous layer was washed with chloroform (500ml), and the organic layers were combined, washed with water (200 ml),dried with magnesium sulfate, and concentrated under reduced pressure toan amber oil. This was dissolved in isopropyl alcohol (50 ml) with heat.To the resulting solution cooled to room temperature was added 23.8 mlof 1N HCl in diethyl ether. A white solid formed, and after 1 hour theresulting mixture was cooled to below 0° C. for 2 hours. The resultingwhite solid was filtered off and washed with cold isopropyl alcohol andthen with diethyl ether. The white solid was then dried under vacuum at80° C. for 2 days to provide 6.00 g of2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-aminehydrochloride, m.p. 181.0-183.0° C.

[0209] Analysis: Calculated for C₁₄H₂₂N₄O (1.00 HCl): %C, 56.27; %H,7.76; %N, 18.75

[0210] Found: %C, 56.33; %H, 7.81; %N, 18.68.

Example 5

[0211] Part A

[0212] 2-Chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine

[0213] 2,4-Dichloro-6-methyl-3-nitropyridine (7.01 g), anhydrousdimethylformamide (70 ml), and triethylamine (4.72 ml) were combined andcooled to 0° C. 2-Methylpropylamine (3.36 ml) was added dropwise to theresulting mixture. The reaction was stalled at 75% completion, asdetermined by HPLC and TLC monitoring, after 16 hours. Thedimethylformamide was removed from the resulting reaction mixture underreduced pressure, and the resulting oil was dissolved in ethyl acetate.The ethyl acetate solution was washed with water, dried with magnesiumsulfate, and the solvent was removed under reduced pressure. Theresulting yellow oil was put through a column of silica using 90/10hexane/ethyl acetate. After removing the solvent from the resultingeluted solution, the resulting yellow oil (5.0 g) was dried under highvacuum and used in the next step.

[0214] Part B

[0215] 2-Chloro-N⁴-(2-methylpropyl)-6-methylpyridin-3,4-diamine

[0216] 2-Chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine (5.00g) from Part A, toluene (100 ml), and 5% platinum on carbon (3.5 g) wereadded to a Parr shaker and placed on a hydrogenator at a hydrogenpressure of 345 kPa for 4 hours. The reaction, monitored by HPLC, wascomplete, and the resulting reaction mixture was filtered through afluted filter paper and then through a folded No. 2 Whatman filter. Thesolvent was removed from the filtrate under reduced pressure, and theresulting oil (4.14 g) was carried on to the next step.

[0217] Part C

[0218]N-[2-Chloro-4-(2-methylpropylamino)-6-methylpyridin-3-yl]-2-ethoxyacetamide

[0219] Anhydrous dichloromethane (300 ml),2-chloro-N⁴-(2-methylpropyl)-6-methyl pyridin-3,4-diamine (4.14 g) fromPart B and triethylamine (2.93 ml) were combined and cooled to 0° C. Tothe resulting mixture was added dropwise ethoxyacetyl chloride (2.49 g).After 1 hour the resulting reaction mixture was allowed to warm to roomtemperature. After 2 hours, the reaction, monitored by HPLC, wascomplete, and the solvent was removed under reduced pressure. Theresulting yellow oil was dissolved in ethyl acetate, and the resultingsolution was washed with water. The organic layer was dried withmagnesium sulfate and concentrated to a yellow oil under reducedpressure. The yellow oil was put through a column of silica gel using20/80 ethyl acetate/hexane. NMR analysis of the oil obtained afterremoval of the solvent under reduce pressure indicated desired product(3.64 g) of good purity for use in the next step.

[0220] Part D

[0221]4-Chloro-2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridine

[0222]N-[2-Chloro-4-(2-methylpropylamino)-6-methylpyridin-3-yl]-2-ethoxyacetamide(3.64 g), anhydrous toluene (100 ml), and phosphorus oxychloride (10.2ml) were combined in a sealed glass tube and heated to 135° C. for 16hours. The resulting reaction mixture was cooled, and the phosphorusoxychloride and toluene were removed under reduced pressure. Theresulting black oil was dissolved in ethyl acetate, and the resultingsolution was washed with saturated aqueous sodium bicarbonate. The basicaqueous layer was then washed with ethyl acetate. The organic layerswere combined and concentrated to a black oil under reduced pressure.The oil was put through a column of silica gel using 60/40 ethylacetate/hexane. The resulting eluted solution was dried under reducedpressure to a brown oil, which solidified after sitting for 48 hours.NMR analysis of the resulting product (2.59 g) indicated only minorimpurities, and the product was carried on to the next step.

[0223] Part E

[0224]2-(Ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-H-imidazo[4,5-c]pyridine

[0225] To a chilled solution of diglyme (2 ml) and sodium hydride (60%in oil) (0.15 g) was added phenol (0.035 g) in portions. Hydrogen wasgiven off and the reaction was allowed to continue for 1 hour.4-Chloro-2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridine(0.10 g) from Part D was added to the resulting reaction mixture. Theresulting dark brown solution was heated to reflux for two days, cooledto room temperature, and dissolved in ethyl acetate. The ethyl acetatesolution was washed with water, and the organic layer was dried withmagnesium sulfate and concentrated under reduced pressure.

[0226] The above was repeated using 20 ml diglyme, 0.40 g sodium hydride(60% in oil), 0.88 g phenol, and 2.49 g starting material. Afterreluxing for 5 days the reaction was 65% complete, but not progressing.The resulting reaction mixture was cooled to room temperature, andtreated as described above. The material from both runs was combined andthen purified by column chromatography using 20/80 ethyl acetate/hexaneto give starting material (0.85 g) and product (1.72 g).

[0227] The recovered starting material (0.85 g) was reacted as describedabove using 5 ml diglyme, 0.14 g sodium hydride (60% in oil), and 0.30 gphenol. When the addition of starting material to the sodium phenoxidesolution was complete the resulting dark brown reaction solution washeated to reflux for 24 hours. The reaction was complete as determinedby HPLC, and the resulting reaction solution was cooled to roomtemperature and treated as described above, except that the brown oilwas passed through a column using 30/70 ethyl acetate/hexane. Theresulting solution was concentrated under reduced pressure to give abrown oil product (0.79 g), which was found to be pure by TLC analysis.Combined product from each of the above three preparations was used inthe next step.

[0228] Part F

[0229]2-(Ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine

[0230] A sealed glass tube containing2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine(2.51 g) from Part E and ammonium acetate (25.1 g) was heated to 150° C.After 36 hours, TLC monitoring indicated that the reaction was complete.The resulting reaction mixture was cooled and then dissolved in ethylacetate. The ethyl acetate solution was washed with 25% aqueous sodiumhydroxide. The resulting organic layer was dried with magnesium sulfate,and concentrated under reduced pressure to an orange oil. The oil wasput through a column using 95/5 ethyl acetate/methanol, providing goodseparation. The oil recovered from the product fraction was dissolved inisopropyl alcohol, to which 1M HCl in diethyl ether was added. A whitesolid formed. More diethyl ether was added, and the white solid wasfiltered and dried under vacuum at 80° C. for 5 hours. The resultingsolid was dissolved in water (50 ml), and the pH was adjusted to 11using sodium carbonate. An oil separated and was extracted withdichloromethane. The resulting dichloromethane solution was dried withmagnesium sulfate and concentrated under reduced pressure to a clearoil. The oil was triturated with methanol, and the resulting solid wasdissolved in diethyl ether. The diethyl ether solution was subjected tohigh vacuum at room temperature to dry the product. The resultingpartially solidified product was solidified by cooling with an isopropylalcohol/dry ice bath to provide2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine,m.p. 77.0-79.0° C.

[0231] Analysis: Calculated for C₁₄H₂₂N₄O: %C, 64.09; %H, 8.45; %N,21.36

[0232] Found: %C, 63.84; %H, 8.32; %N, 21.08.

[0233] The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. Variousmodifications and alterations to this invention will become apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. It should be understood that this invention is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein and that such examples and embodiments arepresented by way of example only with the scope of the inventionintended to be limited only by the claims set forth herein as follows.

What is claimed is:
 1. A process for preparing a1H-imidazo[4,5-c]pyridin-4-amine compound of Formula I

or a pharmaceutically acceptable salt thereof wherein R₁ is selectedfrom hydrogen; CHR_(x)R_(y) wherein R_(x) is hydrogen and R_(y) isselected from alkyl or cyclic alkyl containing one to ten carbon atoms,straight chain or branched chain alkenyl containing two to ten carbonatoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkylwherein the alkoxy moiety contains one to four carbon atoms and thealkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl;and —C—CR_(z)R_(z) wherein each R_(z) is independently alkyl or cyclicalkyl of one to six carbon atoms; R₂ is selected from hydrogen; alkylcontaining one to eight carbon atoms; hydroxyalkyl containing one to sixcarbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to fourcarbon atoms and the alkyl moiety contains one to six carbon atoms;benzyl, phenylethyl; and phenyl; the benzyl, phenylethyl, or phenylsubstituent being optionally substituted on the benzene ring by a moietyselected from methyl, methoxy, and halogen; and morpholinoalkyl whereinthe alkyl moiety contains one to four carbon atoms; R₃ and R₄ areindependently selected from hydrogen and alkyl of one to five carbonatoms; which process comprises the steps of: (1) providing a compound ofFormula II

 wherein R₃ and R₄ are as described above; (2) reacting the compound ofthe Formula II with a chlorinating agent to provide a compound ofFormula III

(3) reacting the compound of the Formula II with a compound of formulaR₁NH₂, wherein R₁ is as defined above, to provide a compound of FormulaIV

(4) reacting the compound of the Formula IV with an alkali metalphenoxide to provide a compound of Formula V

(5) reducing the compound of the Formula V to provide a compound ofFormula VI

(6) reacting the compound of the Formula VI with a carboxylic acid ofthe formula R₂CO₂H; an equivalent thereof selected from thecorresponding acyl halide, R₂C(O-alkyl)₃, andR₂C(O-alkyl)₂(O(O═)C-alkyl); or a mixture thereof, wherein R₂ is asdefined above and each alkyl contains 1 to 8 carbon atoms, to provide acompound of Formula VIII

 and (7) reacting the compound of the Formula VIII with an aminatingagent to provide a compound of the Formula I.
 2. The process accordingto claim 1, wherein in step (6) the compound of the Formula VI isreacted with the carboxylic acid of the formula R₂CO₂H; an equivalentthereof selected from the corresponding acyl halide, R₂C(O-alkyl)₃, andR₂C(O-alkyl)₂(O(O=)C-alkyl); or a mixture thereof; in the presence ofcyclization conditions to provide a compound of the Formula VIII.
 3. Theprocess of claim 1, wherein step (6) includes the steps of: (6a)reacting the compound of the Formula VI with a carboxylic acid of theformula R₂CO₂H or the corresponding acyl halide to provide a compound ofFormula VII

 and (6b) subjecting the compound of the Formula VII to cyclizationconditions, during step (6a) or subsequent to the completion of step(6a), to provide a compound of the Formula VIII.
 4. The process of claim3, wherein in step (6a) the carboxylic acid equivalent is thecorresponding acyl halide of R₂CO₂H, and in step (6b) the cyclizationconditions include heating to an elevated temperature and a conditionselected from the presence of pyridine, and the presence of pyridinewith pyridine hydrochloride.
 5. The process of claim 4, wherein the acylhalide is ethoxyacetyl chloride, and wherein the cyclization conditionsinclude an elevated temperature and the presence of pyridine during step(6a).
 6. The process of claim 1, further comprising the step ofisolating the compound of Formula I or a pharmaceutically acceptablesalt thereof.
 7. The process of claim 1, wherein R₁ is selected from2-hydroxy-2-methylpropyl and 2-methylpropyl.
 8. The process of claim 1,wherein R₂ is ethoxymethyl.
 9. The process of claim 1, wherein R₃ and R₄are independently hydrogen or methyl.
 10. The process of claim 1,wherein R₃ and R₄ are both methyl.
 11. The process of claim 1, whereinR₁ is selected from 2-hydroxy-2-methylpropyl and 2-methylpropyl, andwherein R₂ is ethoxymethyl.
 12. The process of claim 11, wherein R₃ andR₄ are independently hydrogen or methyl.
 13. The process of claim 1,wherein the compound of Formula I is selected from

and pharmaceutically acceptable salts thereof.
 14. The process of claim1, wherein the alkali metal phenoxide is sodium phenoxide.
 15. Theprocess of claim 1, wherein the chlorinating agent is phosphorusoxychloride.
 16. The process of claim 1, wherein the compound of theformula R₁NH₂ is selected from 2-hydroxy-2-methylpropylamine and2-methylpropylamine.
 17. The process of claim 1, wherein in step (5) thecompound of Formula V is reduced with a heterogeneous hydrogenationcatalyst.
 18. The process of claim 17, wherein the heterogeneoushydrogenation catalyst is selected from platinum on carbon and palladiumon carbon.
 19. The process of claim 1, wherein the aminating agent isammonium acetate.
 20. A process for preparing a1H-imidazo[4,5-c]pyridin-4-amine compound of Formula I

or a pharmaceutically acceptable salt thereof wherein R₁ is selectedfrom hydrogen; CHR_(x)R_(y) wherein R_(x) is hydrogen and R_(y) isselected from alkyl or cyclic alkyl containing one to ten carbon atoms,straight chain or branched chain alkenyl containing two to ten carbonatoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkylwherein the alkoxy moiety contains one to four carbon atoms and thealkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl;and —C═CR_(z)R_(z) wherein each R_(z) is independently alkyl or cyclicalkyl of one to six carbon atoms; R₂ is selected from hydrogen; alkylcontaining one to eight carbon atoms; hydroxyalkyl containing one to sixcarbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to fourcarbon atoms and the alkyl moiety contains one to six carbon atoms;benzyl; phenylethyl; and phenyl; the benzyl, phenylethyl, or phenylsubstituent being optionally substituted on the benzene ring by a moietyselected from methyl, methoxy, and halogen; and morpholinoalkyl whereinthe alkyl moiety contains one to four carbon atoms; R₃ and R₄ areindependently selected from hydrogen and alkyl of one to five carbonatoms; which process comprises the steps of: (1) providing a compound ofFormula II

 wherein R₃ and R₄ are as described above; (2) reacting the compound ofthe Formula II with a chlorinating agent to provide a compound ofFormula III

(3) reacting the compound of the Formula III with a compound of formulaR₁NH₂, wherein R₁ is as defined above, to provide a compound of FormulaIV

(4) reducing the compound of the Formula IV to provide a compound ofFormula IX

(5a) reacting the compound of the Formula IX with a carboxylic acid ofthe formula R₂CO₂H; an equivalent thereof selected from thecorresponding acyl halide, R₂C(O-alkyl)₃, andR₂C(O-alkyl)₂(O(O=)C-alkyl); or a mixture thereof, wherein R₂ is asdefined above and each alkyl contains 1 to 8 carbon atoms to provide acompound of Formula XI

(6) reacting the compound of the Formula XI with an alkali metalphenoxide to provide a compound of Formula VIII

 and (7) reacting the compound of the Formula VIII with an aminatingagent to provide the compound of the Formula I.
 21. The processaccording to claim 20, wherein in step (5) the compound of the FormulaIX is reacted with the carboxylic acid of the formula R₂CO₂H; anequivalent thereof selected from the corresponding acyl halide,R₂C(O-alkyl)₃, and R₂C(O-alkyl)₂(O(O═)C-alkyl); or a mixture thereof; inthe presence of cyclization conditions, to provide a compound of theFormula XI.
 22. The process according to claim 20, wherein step (5)includes the steps of: (5a) reacting the compound of the Formula IX witha carboxylic acid of the formula R₂CO₂H or the corresponding acyl halideto provide a compound of Formula X

 and (5b) subjecting the compound of the Formula X to cyclizationconditions, during step (5a) or subsequent to the completion of step(5a) to provide a compound of the Formula XI.
 23. The process of claim20, further comprising the step of isolating the compound of Formula Ior a pharmaceutically acceptable salt.
 24. The process of claim 20,wherein R₁ is selected from 2-hydroxy-2-methylpropyl and 2-methylpropyl.25. The process of claim 20, wherein R₂ is ethoxymethyl.
 26. The processof claim 20, wherein R₃ and R₄ are independently hydrogen or methyl. 27.The process of claim 20, wherein R₃ and R₄ are both methyl.
 28. Theprocess of claim 20, wherein R₁ is selected from2-hydroxy-2-methylpropyl and 2-methylpropyl, and wherein R₂ isethoxymethyl.
 29. The process of claim 28, wherein R₃ and R₄ areindependently hydrogen or methyl.
 30. The process of claim 20, whereinthe compound of Formula I is selected from

and pharmaceutically acceptable salts thereof.
 31. The process of claim20, wherein in step (5a) the carboxylic acid equivalent is thecorresponding acyl halide of R₂CO₂H, and in step (5b) the cyclizationconditions include an elevated temperature and the presence ofphosphorus oxychloride.
 32. The process of claim 31, wherein the acylhalide is ethoxyacetyl chloride.
 33. The process of claim 20, whereinthe alkali metal phenoxide is sodium phenoxide.
 34. The process of claim20, wherein the chlorinating agent is phosphorus oxychloride.
 35. Theprocess of claim 20, wherein the compound of the formula R₁NH₂ isselected from 2-hydroxy-2-methylpropylamine and 2-methylpropylamine. 36.The process of claim 20, wherein in step (4) the compound of Formula IVis reduced with a heterogeneous hydrogenation catalyst.
 37. The processof claim 36, wherein the heterogeneous hydrogenation catalyst isplatinum on carbon.
 38. The process of claim 20, wherein the aminatingagent is ammonium acetate.
 39. A compound selected from the formulae

and pharmaecutically acceptable salts thereof.